PROJECT SUMMARY Growing evidence suggests that the cognitive symptoms underlying many psychiatric disorders, including addiction, result from a failure to appropriately learn about and/or anticipate potential future events. Indeed, deficits in the prospective consideration of potential rewarding events have been detected in patients diagnosed with addiction, accounting for their inability to limit use despite deleterious consequences. Similar deficits have been identified in patients diagnosed with mental illnesses comorbid with addiction, such as depression, anxiety, and schizophrenia. These mental illnesses are major intractable public health problems in the US, accounting for hundreds of billions of dollars in costs associated with health care, crime, incarceration and law enforcement. Effective approaches to prevent and/or treat these conditions are, therefore, badly needed. The goal of this research is to expose the neural circuits required to learn predictive relationships and to use this information to generate expectations about the future, in order to gain insight into how pathological states arise and determine what can be done to combat them. Addictive substances are thought to hijack the brain systems that normally support adaptive decision making, resulting in maladaptive choices. Adaptive decision making requires accurate prospective consideration of possible future events. Prior encoding of specific stimulus-reward associative memories enables this prospective consideration by allowing the mental simulation (i.e., representation) of possible future rewarding events. Recent studies in rodents and humans have indicated that the basolateral amygdala (BLA) might be a brain region crucial for learning these associations, but precisely how and the neural circuitry through which it achives this function are unknown. The proposed research provides a critical, in-depth, and hypothesis-driven investigation of the contribution of the BLA and its reciprocal connections with the orbitofrontal cortex, a region implicated in decision making, to stimulus-reward encoding and subsequent retrieval of this information to guide adaptive behavior and choice. This will be achieved through a multi-faceted and integrative neural recording and manipulation approach. We will combine projection-specific activity monitoring, tag and capture techniques for manipulation of specific event-activated neuronal ensembles, and behavioral procedures with translational relevance to symptoms of human mental illness to uncover the function of amgydala-cortical loops in adaptive reward-guided behavior and decision making.